The overall goal of this Phase 2 STTR is to develop and commercialize a novel approach for allergen specific immunotherapy as a treatment for severe food allergy. Currently treatment to prevent severe food reactions is a major unmet need. There is no effective therapy, the only treatment being strict avoidance and emergency measures should an exposure occur. The molecules that comprise this platform are genetically engineered food allergen-human Fc?1 chimeric fusion proteins. Having achieved the production of the first peanut-human chimeric (AraH2)2-Fc?1, we now plan to define the optimal type of chimeric protein or mixture of proteins necessary for specific peanut immunotherapy. This Phase 2 proposal will serve to accomplish the major milestones necessary for commercialization of this therapeutic approach for severe food allergy. In Phase 1, the lead molecule (AraH2)2-Fc?1 (AraH2-G) was constructed and tested as a model for other peanut allergens. In Phase 2, we will define and generate the optimal product for IND-enabling studies and clinical development by accomplishing the following Specific Aims. In Aim 1 we will establish research-level expression systems and characterize several types of the key peanut allergen-Fc?1 proteins. These will include (a) production of classic dimers, beyond (AraH2)2-G; (b) monomeric AraH-G proteins in which a single AraH protein is joined to the Fc?1 dimer; (c) polymeric (AraH2+AraH1)2-G; and (d) double-dimers, in which an AraH dimer is joined to two Fc?1 dimers. These variants may improve manufacturability of the final product and will be tested for key feature of an improved safety profile in Aim 3. In Aim 2 we will test the hypothesis that cross-desensitization can be generated for AraH-G proteins. If it does, this strategy could be game changing as it would simplify overall food allergy immunotherapy, speed product commercialization and decrease the cost of the therapy. Aim 3 will define the optimal clinical candidate(s) chimeric peanut-human FcG protein(s) through a series of in vitro and in vivo experiments defining both their safety and efficacy; safety being their inability to act as allerge while efficacy being their ability to induce tolerance to peanut in previously sensitized animals. The exact experiments and the likely lead compound(s) will be greatly impacted if we observe cross-desensitization in Aim 2. Finally, in Aim 4 we will establish stable high-expressing GMP-quality cell lines producing the final clinical candidate(s) identified by accomplishing Specific Aims 1-3. Success in Phase 2 will set the stage for production of material for formal IND-enabling studies and GMP material for a first-in human trial designed to demonstrate the lack of allergenicity of the clinical candidate. If successful with peanut, extending this approach to othe key food antigens will be relatively straightforward.